YTX-7739 Trials Suspended, ENSURE-2 Study of IMU-838 Initiated, Behavioral Involvement of FTD in ALS

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Welcome to this special edition of Neurology News Network. I’m Marco Meglio.

The FDA has placed a partial clinical hold on multidose clinical trials of YTX-7739, a disease-modifying therapy for the treatment of Parkinson disease (PD), Yumanity Therapeutics recently announced. The hold was initiated in response to the company’s investigational new drug (IND) application, which was submitted in December 2021.The hold suspends initiation of multiple dose trials of the treatment in the US until questions from the FDA have been addressed, with Yumanity anticipating additional detail from the FDA in the next 30 days. YTX-7739 has previously been assessed in healthy patients, with results reported from 14- and 28-day multiple dosing studies, as well as in patients with PD in a 28-day multiple dose clinical study. The treatment is designed to penetrate the blood-brain barrier (BBB), then inhibiting the activity of stearoyl-CoA desaturase (SCD), a novel target. By inhibiting SCD, YTX-7739 controls and upstream process in the α-synuclein pathological cascade, and in preclinical cellular and animal models, it has been shown to rescue or prevent toxicity, according to Yumanity.

The first patient has been enrolled in the phase 3 ENSURE-2 pivotal clinical trial of IMU-838, a dihydroorotate dehydrogenase inhibitor vidofludimus calcium, for the treatment of relapsing multiple sclerosis (RMS), Immunic recently announced. The trial is a twin of ENSURE-1, with both comprising the ENSURE program to evaluate the efficacy, safety, and tolerability of IMU-838. The FDA cleared an investigational new drug (IND) application for the phase 3 program in July 2021, and both trials are aimed at providing additional reliable data with the potential to speed up regulatory IND approval. In ENSURE-1, which began in November 2021, and ENSURE-2, 30-mg daily doses of IMU-838 are compared with placebo in patients with RMS, enrolling a combined total of 1050 adult participants at over 100 sites in 15 countries. The primary end point is cited as time to first relapse up to 72 weeks. Secondary end points are noted as volume of T2-lesions, time to confirmed disability progression, time to sustained clinically relevant change sin cognition, and percentage of whole brain volume change, grey matter volume, and white matter volume.

Although previous literature has shown overlaps between ALS and frontotemporal dementia (FTD), the possible cognitive and/or behavioral involvement of FTD may be its own phenotype and not a product of disease worsening, according to new results from a multiparametric study. All told, those with ALS with cognitive and or/behavioral involvement (ALS-ci/bi) showed a rearrangement of the functional networks, which was divergent from those with solely motor deficits (ALS-cn), with the enhanced functional connectivity within motor areas and decreased connectivity in the frontotemporal networks. The concomitant absence of significant structural alterations, compared with the ALS-cn group, supported a maladaptive role of such functional rearrangements in ALS-ci/bi, which had been previously hypothesized. Additional results on the distribution analysis indicated that most patients with ALS-cn-like patterns (81%) were characterized by a greater damage within the motor network, specifically among the sensorimotor– basal ganglia connections, relative to bvFTD cases.

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